title: Interaction between Na+/phosphate-cotransporter and the adrenoceptors in myocardial depression.
abstract: The primary objective of this study was to test the hypothesis that an increase in the alpha1-adrenoceptor tone would potentiate the myocardial biphasic contractile response to inorganic phosphate [Pi, the substrate of Na/Pi-cotransporter (NP)]. A second aim was to determine whether activation of alpha1-adrenoceptor is necessary for the NP-mediated increase in myocardial contractility (+dP/dt). Earlier study from this laboratory showed that high concentration of Pi (10 mM) produces a biphasic contractile response: initial increase in +dP/dt was followed by decline. In another study, Pi (3.5 mM) potentiated phenylephrine (PHE)-induced increase in +dP/dt. The alpha1-adrenoceptor was not blocked in these studies, and it can still be activated by the electrical stimulation of the sympathetic nerve terminals to the heart. Additionally, alpha1-adrenoceptor-activated increases in the activity of NP have been reported in numerous studies in noncardiac tissues and cell lines; therefore it is not clear whether Pi-induced increase in +dP/dt occurs only in the presence of alpha1-adrenoceptor activation. This study was performed by using isolated perfused rat heart in the condition of controlled extracellular calcium activity (0.72 mM); fixed preload (15 mm Hg); and constant heart rate (280 beats/min) and coronary flow (8 ml/min). The electronically differentiated value of the left ventricular pressure (LVP) signal was used as an index of myocardial contractility. The data show that activation of the alpha1-adrenoceptor is not necessary for the Pi-induced increase in +dP/dt (i.e., NP-mediated increase in +dP/dt has both the alpha1-adrenoceptor-dependent and alpha1-adrenoceptor-independent components. The interaction between alpha1-adrenoceptor agonist (PHE) and Pi (10 mM) did not produce a biphasic myocardial contractile response in the presence of propranolol. Because our earlier data on myocardial biphasic contractile response to 10 mM Pi was obtained when neither the beta- nor the alpha-adrenoceptor was blocked, we carried out more studies to see whether beta-adrenoceptor plays a role in this Pi-induced biphasic response. When both the alpha- and beta-adrenoceptors were activated with norepinephrine (NE), myocardial depression by high Pi concentration was markedly potentiated. This myocardial depression did not occur in the presence of phosphonoformate, a selective inhibitor of NP. It also did not occur when alpha1-adrenoceptor was blocked. Our data suggest that alpha1- and beta-adrenoceptors do not interact with the cardiac NP to potentiate the Pi-induced biphasic contractile response, but they interact in a manner that potentiates Pi-induced myocardial depression.
authors.affiliation: Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo 43699-0008, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Onwochei
authors.forename: A O
authors.initials: AO
authors.lastname: Ofori
authors.forename: I L
authors.initials: IL
authors.lastname: Agodoa
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D003864:Depression, Chemical; D004347:Drug Interactions; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D011433:Propranolol; D009638:Norepinephrine